Organization of the DYRK1A interactome through docking domains: searching for novel targeting approaches

DYRK1A is human chromosome 21 (HSA21) gene that encodes a protein kinase, whose expression is increased in Down syndrome (DS) individuals.  Aberrant DYRK1A expression is implicated in several pathological traits of DS, including increased risk of childhood leukemia, skeletal abnormalities, intellectual disability, and retinal defects and it has therefore become one of the few HSA21 genes selected for therapeutic approaches in DS.  

DYRK1A kinase activity mostly relies on changes induced by phosphorylation of its substrates; however, not very much is known about its in vivo substrates. In addition, associations between a kinase and its substrates are often low affinity, and therefore kinases use dedicated protein–protein interaction surfaces, known as docking sites, to facilitate spatial/temporal regulation of downstream phosphorylation. Since such information is missing for DYRK1A, this project will use a proteomic proximity label approach to identify transient/low affinity interactors of DYRK1A and subsets of interacting proteins whose recruitment to the kinase depend on different protein motifs. Furthermore, chemical genetics will be employed to identify direct targets of the DYRK1A kinase activity.  

The combination of a protein-protein interaction network and the phospho-proteomics data will allow the identification of those targets regulated by DYRK1A and provide insights into the physical organization of the DYRK1A interactome. Altogether, the generated data will contribute to advance in the understanding of DYRK1A involvement in DS.